Elsevier

Biological Psychiatry

Volume 68, Issue 10, 15 November 2010, Pages 903-912
Biological Psychiatry

Archival Report
YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer's Disease

https://doi.org/10.1016/j.biopsych.2010.08.025Get rights and content

Background

Disease-modifying therapies for Alzheimer's disease (AD) would be most effective during the preclinical stage (pathology present, cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design.

Methods

AD-associated changes in cerebrospinal fluid (CSF) were measured using two-dimensional difference gel electrophoresis and liquid chromatography tandem mass spectrometry. Subsequently, CSF YKL-40 was measured by enzyme-linked immunosorbent assay in the discovery cohort (n = 47), validation cohort (n = 292) with paired plasma samples (n = 237), frontotemporal lobar degeneration (PSP; n = 9), and progressive supranuclear palsy (PSP; n = 6). Immunohistochemistry was performed to identify source(s) of YKL-40 in human AD brain.

Results

Discovery and validation cohorts, showed higher mean CSF YKL-40 in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) versus control subjects (CDR 0) and PSP subjects. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR > 0 conversion), as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau 181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 versus CDR 0, and correlated with CSF levels. YKL-40 immunoreactivity labeled astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition.

Conclusions

These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD and, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.

Section snippets

Discovery Cohort

Subjects (n = 48), community-dwelling volunteers from University of Washington (n = 18), Oregon Health and Science University (n = 11), University of Pennsylvania (n = 11), and University of California San Diego (n = 8), were 51 to 87 years of age and in good general health, having no other neurological, psychiatric, or major medical diagnoses that could contribute importantly to dementia or use of exclusionary medications within 1 to 3 months of lumbar puncture (LP) (e.g., neuroleptics,

Proteomic Analysis Identifies YKL-40 as Increased in AD CSF

To identify new candidate biomarkers for AD, we used an unbiased proteomics approach, 2-D DIGE LC-MS/MS (22, 23), to compare the concentrations of CSF proteins in individuals with mild dementia (CDR 1, n = 24) of the Alzheimer's type with those in individuals without dementia (CDR 0, n = 24). The two groups differed with respect to age at LP and gender (CDR 0: 64.8 years, 38% female; CDR 1: 72.8 years, 54% female). From this proteomic analysis, we identified 47 proteins that differed in

Discussion

This study suggests that CSF YKL-40, a novel inflammatory biomarker for AD, is increased in AD and, together with Aβ42, will assist in prognosis of patients and clinical trial participants who are under examination for the preclinical and early clinical stages of AD.

Having identified CSF YKL-40 as a potential AD biomarker through nonbiased proteomics, we verified this finding using a commercially available ELISA and, more importantly, validated the results in a much larger, independent cohort.

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    Authors RC-S and RJP contributed equally to this work.

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